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• W4242636494 abstract "We thank Luukkonen et al1Luukkonen P.K. et al.Gastroenterology. 2021; 160: 1874-1875Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar for their letter revealing the importance of the Pi∗MZ variant in the general population. Although several prominent studies demonstrated the relevance of the Pi∗Z variant in selected cohorts2Propst T. et al.Ann Intern Med. 1992; 117: 641-645Crossref PubMed Scopus (90) Google Scholar, 3Fischer H.P. et al.J Hepatol. 2000; 33: 883-892Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 4Strnad P. et al.N Engl J Med. 2020; 382: 1443-1455Crossref PubMed Scopus (69) Google Scholar, 5Schaefer B. et al.Liver Transplant. 2018; 24: 744-751Crossref PubMed Scopus (31) Google Scholar as well as in large cohorts of individuals suffering from alcoholic or nonalcoholic fatty liver disease,6Abul-Husn N.S. et al.N Engl J Med. 2018; 378: 1096-1106Crossref PubMed Scopus (296) Google Scholar,7Strnad P. Buch S. Hamesch K. et al.Gut. 2019; 68: 1099-1107Crossref PubMed Scopus (62) Google Scholar these manuscripts neither focused on the general population nor on liver-related mortality. To further extend the observations made by Luukkonen et al,1Luukkonen P.K. et al.Gastroenterology. 2021; 160: 1874-1875Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar we turned to the “UK Biobank” (UKB), a community-based cohort study that recruited >500,000 participants at 22 UK centers between 2006 and 2010. At baseline, all participants provided a variety of demographic and physical measures, whereas the coexisting diagnoses were collected through linkage to medical reports. In addition, most UKB participants were subjected to genome-wide genotyping with Axiom arrays that included the Pi∗Z variant (rs28929474). UKB also prospectively receives death notifications (age at death and primary International Classification of Diseases diagnosis that led to death) through linkage to national death registries until November 2020. The UKB included 17,179 Pi∗MZ individuals and 426,994 controls without presence of either the Pi∗Z or the Pi∗S variant (noncarriers) with available long-term follow-up and reported data on mortality. During the median follow-up of 11.4 years, 1169 (6.8%) of 17,179 Pi∗MZ participants and 26,786 (6.3%) of 426,994 noncarriers died. Pi∗MZ individuals had higher liver-related mortality (ie, International Classification of Diseases codes K70–76) (0.2% vs 0.1%; adjusted hazard ratio [aHR] 1.79; 95% confidence interval [CI] 1.21–2.64; adjusted for age, sex, and body mass index [BMI]), whereas the incidence of non–liver-related death was similar in Pi∗MZ individuals and noncarriers (6.6% vs 6.2%; aHR 1.05; 95% CI 0.98–1.12). Notably, compared with the remainder of the group (n = 17,150), Pi∗MZ subjects with liver-related death (n = 29) were significantly older, more often obese and diabetic, and more frequently displayed features of metabolic syndrome. They were also predominantly of male sex and reported higher alcohol consumption (Table 1).Table 1Comparison of Pi∗MZ Subjects With Liver-related Death (n = 29) vs Pi∗MZ Without Liver-related Death (n = 17,150)Pi∗MZ without liver-related death n = 17,150Pi∗MZ with liver-related death n = 29P value (univariable)Age (y)56.9 ± 8.161.0 ± 7.4.005BMI (kg/m2)27.3 ± 4.729.5 ± 6.0.014BMI ≥30 kg/m2 (%)aHazard ratio (HR) 3.38 (95% confidence interval [CI] 1.57–7.29).3057.002Sex (% male)bHR 7.40 (95% CI 2.57–21.32).4586.00001Diabetes mellitus (%)cHR 10.14 (95% CI 4.41–23.30).4291.8879E-10Metabolic syndrome (%)dHR 5.49 (95% CI 2.53–11.91).935.000002Alcohol intake (g/d)9.1 ± 11.116.0 ± 18.8.001Relevant alcohol intakeeAlcohol intake >12 g/d women, >24 g/d men. (%)fHR 3.43 (95% CI 1.55–7.59).1334.001Current smoking (%)2.53.5.47NOTE. Bold values indicate significant P-values.BMI, body mass index.a Hazard ratio (HR) 3.38 (95% confidence interval [CI] 1.57–7.29).b HR 7.40 (95% CI 2.57–21.32).c HR 10.14 (95% CI 4.41–23.30).d HR 5.49 (95% CI 2.53–11.91).e Alcohol intake >12 g/d women, >24 g/d men.f HR 3.43 (95% CI 1.55–7.59). Open table in a new tab NOTE. Bold values indicate significant P-values. BMI, body mass index. In line with the data from Luukkonen et al,1Luukkonen P.K. et al.Gastroenterology. 2021; 160: 1874-1875Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Pi∗MZ conferred even higher risk of liver-related death among obese individuals (aHR 2.15; 95% CI 1.29–3.58), while the difference in those with BMI <30 kg/m2 did not reach statistical significance (aHR 1.42; 95% CI 0.77–2.60, both adjusted for age and sex). Notably, diabetes mellitus conferred an even higher risk of liver-related death in Pi∗MZ participants than noncarriers (aHR 2.59; 95% CI 1.19–5.60), whereas the effect in Pi∗MZ individuals without diabetes mellitus was not different from nondiabetic noncarriers (aHR 1.49; 95% CI 0.93–2.41; both adjusted for age, sex, and BMI). The discrepancy to the observations from Luukkonen et al1Luukkonen P.K. et al.Gastroenterology. 2021; 160: 1874-1875Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar might be due to low power of their substantially smaller cohort because diabetes is less frequent than obesity. Similar to the effect of obesity and diabetes, metabolic syndrome conferred the highest risk of liver-related death among Pi∗MZ participants compared with noncarriers (aHR 3.56; 95% CI 1.84–6.87), whereas the effect in Pi∗MZ individuals without metabolic syndrome was similar to noncarriers (aHR 1.39; 95% CI 0.85–2.26; both adjusted for age, sex, and BMI). Apart from these metabolic risk factors, we looked at the potential impact of low/moderate alcohol consumption and smoking that remained unclear. Interestingly, Pi∗MZ individuals with reported relevant daily alcohol intake (>12 g/d women, >24 g/d men) had a significantly higher risk of liver-related death than controls with similar alcohol consumption (aHR 2.32; 95% CI 1.46–3.43), whereas no increased mortality was seen in Pi∗MZ individuals without relevant alcohol intake compared with noncarriers with similar alcohol consumption (aHR 1.73; 95% CI 0.99–2.63; both adjusted for age, sex, and BMI). Again, these data that contrast with the report from Luukkonen et al1Luukkonen P.K. et al.Gastroenterology. 2021; 160: 1874-1875Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar might be due to the larger statistical power of the UKB. Moreover, these findings are in line with the recent report from Åberg et al,8Åberg F. et al.Hepatology. 2020; 71: 835-848Crossref PubMed Scopus (43) Google Scholar showing an increased risk for advanced liver disease that was dependent on the amount of alcohol consumption and apparent even for consumption of 10 to 19 g/d compared with lifetime abstainers. Consistently with Luukkonen et al,1Luukkonen P.K. et al.Gastroenterology. 2021; 160: 1874-1875Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar smoking was rare (2.5% of Pi∗MZ subjects) and did not significantly modify the effect of Pi∗MZ on liver-related death (aHR 1.82; 95% CI 0.28–9.08 in smokers; aHR 1.81; 95% CI 0.98–2.21 in nonsmokers; both adjusted for age, sex, and BMI). In conclusion, both the data from Luukkonen et al1Luukkonen P.K. et al.Gastroenterology. 2021; 160: 1874-1875Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar and the findings presented herein further support the previous observations suggesting that obesity, diabetes mellitus, metabolic syndrome, and alcohol consumption constitute key modifiers in Pi∗MZ-related liver disease.7Strnad P. Buch S. Hamesch K. et al.Gut. 2019; 68: 1099-1107Crossref PubMed Scopus (62) Google Scholar,9Schneider C.V. et al.Gastroenterology. 2020; 159: 534-548.e11Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar These findings are relevant to the clinical routine, because all factors are potentially modifiable and should spur an early diagnosis and appropriate counseling of all Pi∗MZ individuals presenting with signs of liver disease. Pavel Strnad is supported by the German Research Foundation consortium SFB 1382 “Gut-liver axis” and DFG grant STR 1095/6-1 (Heisenberg professorship). This research has been conducted using the UK Biobank Resource under Application Number 47527. The Pi∗MZ Allele in Alpha-1 Antitrypsin Increases Liver-Related Outcomes in a Population-Based StudyGastroenterologyVol. 160Issue 5PreviewWe read with great interest the article by Schneider et al1 on the effect of the Pi∗Z allele in alpha-1 antitrypsin peptide (AAT) on liver phenotypes that, contrary to current dogma, demonstrated that heterozygous Pi∗Z allele carriers are also at risk for liver disease. However, limitations raised by the authors themselves include the cross-sectional study design, with inability to prove cause-and-effect relationships, and potential selection bias. The authors call for large longitudinal population-based studies with clinical liver-related outcomes to overcome these limitations and validate their findings. 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